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Oncotarget. 2016 Sep 13;7(37):59260-59272. doi: 10.18632/oncotarget.10610.

CRLF2 over-expression is a poor prognostic marker in children with high risk T-cell acute lymphoblastic leukemia.

Author information

1
Centro Ricerca M. Tettamanti, Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
2
Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Milan, Italy.
3
Clinica Pediatrica, Università di Milano Bicocca, Fondazione MBBM/Ospedale San Gerardo, Monza, Italy.
4
Laboratory of Onco-Hematology, Department SDB, Università di Padova, Padova, Italy.
5
Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
6
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and EMBL/Medical Faculty Molecular Medicine Partnership Unit, Heidelberg, Germany.
7
Microscopy and Image Analysis Consortium, Università di Milano-Bicocca, Monza, Italy.
8
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
9
Pediatric Onco-Hematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy.
10
Pediatric Oncology Service, Pediatric Department of 2nd University of Naples, Naples, Italy.
11
Department of Pediatric Hematology/Oncology, IRCCS Ospedale Bambino Gesù, Rome - University of Pavia, Pavia, Italy.
12
Center of Pediatric Hematology Oncology, Azienda Ospedaliero-Universitaria "Policlinico Vittorio Emanuele", Catania, Italy.
13
Hematology/Oncology Unit, G. Gaslini Children's Hospital, Genoa, Italy.
14
Department of Pediatric Hemato-Oncology, Ospedale Pausilipon, Napoli, Italy.
15
Department of Pediatrics, "Lalla Seràgnoli" Hematology-Oncology Unit, University of Bologna, Bologna, Italy.
16
Department of Pediatrics, Division of Pediatric Hematology-Oncology, University "A. Moro" of Bari, Bari, Italy.
17
Division of Hematology, Department of Biotechnologies and Hematology, "Sapienza" University of Rome, Rome, Italy.
18
Pediatric Hematology and Oncology Unit, A.R.N.A.S. Civico, Di Cristina and Benfratelli Hospital, Palermo, Italy.
19
Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany.

Abstract

Pediatric T-ALL patients have a worse outcome compared to BCP-ALL patients and they could benefit from new prognostic marker identification. Alteration of CRLF2 gene, a hallmark correlated with poor outcome in BCP-ALL, has not been reported in T-ALL.We analyzed CRLF2 expression in 212 T-ALL pediatric patients enrolled in AIEOP-BFM ALL2000 study in Italian and German centers.Seventeen out of 120 (14.2%) Italian patients presented CRLF2 mRNA expression 5 times higher than the median (CRLF2-high); they had a significantly inferior event-free survival (41.2%±11.9 vs. 68.9%±4.6, p=0.006) and overall survival (47.1%±12.1 vs. 73.8%±4.3, p=0.009) and an increased cumulative incidence of relapse/resistance (52.9%±12.1 vs. 26.2%±4.3, p=0.007) compared to CRLF2-low patients. The prognostic value of CRLF2 over-expression was validated in the German cohort. Of note, CRLF2 over-expression was associated with poor prognosis in the high risk (HR) subgroup where CRLF2-high patients were more frequently allocated.Interestingly, although in T-ALL CRLF2 protein was localized mainly in the cytoplasm, in CRLF2-high blasts we found a trend towards a stronger TSLP-induced pSTAT5 response, sensitive to the JAK inhibitor Ruxolitinib.In conclusion, CRLF2 over-expression is a poor prognostic marker identifying a subset of HR T-ALL patients that could benefit from alternative therapy, potentially targeting the CRLF2 pathway.

KEYWORDS:

CRLF2; T acute lymphoblastic leukemia; high risk; pediatric leukemia; prognostic marker

PMID:
27449287
PMCID:
PMC5312310
DOI:
10.18632/oncotarget.10610
[Indexed for MEDLINE]
Free PMC Article

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